Children and young adults who were exposed to alcohol during fetal life show emotional disturbances such as depression, anxiety, attention deficit, and hyperactivity. Animal studies have linked the behavioral abnormalities to problems in the stress axis function, particularly the hyperresponsiveness of corticotrophin-releasing hormone (CRH) neuronal activity, to a variety of stressful events. Adaptation to a stressful event depends in part on an individual's ability to produce increased levels of the hormones of the stress axis and to reduce the levels of these hormones once the stressor has subsided. Recent reports indicated that hormone and toxicant exposure at crucial developmental stages results in alteration of key genes, resulting in physiological and/or behavioral changes not only in exposed individuals but also in their offspring. Hence, the question is raised whether epigenetic alterations of the CRH neuronal function are caused by alcohol exposure during the development. We hypothesize that alcohol exposure during development impairs stress axis function by altering DNA methylation and expression of proopiomelanocortin (POMC) gene in beta-endorphin neurons, which regulate CRH secretion from the hypothalamus. The objective of the proposal is to test the hypothesis that alcohol exposure during brain development produces epigenetic transgenerational effect on the stress axis function by altering DNA methylation and mRNA expression of CRH and/or its regulatory POMC genes in the hypothalamus. This will be achieved by identifying whether the stress axis hyperresponsiveness is accompanied by altered DNA methylation of gene-promoter activities in beta-endorphin and/or CRH neurons, and by evaluating whether gene-silencing activity is accompanied by the alteration in the expression of DNA methyltransferases in these neurons in the hypothalamus of offspring exposed to alcohol during the developmental period. Furthermore, whether fetal alcohol exposure induces transgenerational effects on the stress axis function will be studied. The proposed studies should provide a better understanding of the molecular mechanisms responsible for the detrimental effects of alcohol on the development of the neuroendocrine axis of stress and should reveal new putative epigenetic disease biomarkers that may enhance early detection strategies and serve as therapeutic targets for stress axis dysfunction in fetal alcohol exposed patients. PUBLIC HEALTH RELEVANCE: Recent reports have indicated that hormone and toxicant exposure at crucial developmental stages cause an alteration in the function of key genes, resulting in physiological and/or behavioral changes not only in exposed individuals but also in their offspring. Hence, the question is raised whether an inheritance of epigenetic alteration of the corticotrophin releasing hormone neuronal function induced by alcohol exposure during development causing the stress axis dysfunction that leads to various affective disorders in fetal alcohol exposed patients. The goal of this proposal is to determine the epigenetic transgenerational effect of alcohol on the stress axis function in order to identify new putative epigenetic disease biomarkers as well as to develop early detection strategies and therapeutic targets for stress axis disorders in fetal alcohol exposed patients.